Traumatic brain injury (TBI) represents a leading cause of morbidity and mortality among young individuals with ~1.7 million reported TBI cases in the U.S. annually. The number of victims under the influence of alcohol while sustaining a TBI is substantial. It is estimated that 36% to 51% of TBI incidents are associated with prior or concurrent alcohol use. Furthermore, many patients continue to use alcohol after TBI in up to 26% of cases. However, not many preclinical studies have examined the impact of post-injury alcohol exposure on TBI recovery and the underlying mechanisms. TBI produces neuroinflammation characterized by a cascade of events such as activation of glial cells, the release of pro-inflammatory cytokines and chemokines, upregulation of endothelial adhesion molecules, and the infiltration of circulating leukocytes. Our preliminary studies show a rapid increase of pro-inflammatory cytokine and chemokine expression at 6 h and enhanced neutrophil infiltration into the ipsilateral site of injury at 24 h post-TBI. In addition, a disrupion of blood brain barrier was observed at 24 and 72 h after TBI. Sustained inflammation is detrimental and contributes to the pathophysiological sequelae post-TBI. Alcohol exposure is a factor involved in exacerbated inflammation, and our preliminary data demonstrate that alcohol intoxication at the time of TBI prolonged the pro-inflammatory cytokine and chemokine mRNA expression at 24 h post-TBI. Therefore, we predict that post-injury alcohol exposure will enhance the neuroinflammatory cascade and prevent the resolution of inflammatory response to TBI. Moreover, prolonged inflammation may cause further brain damage and thus delay the neurological recovery post TBI. This is supported by our preliminary data that show impaired neurological recovery under the influence of post-injury alcohol exposure. Taken together, the literature and our preliminary data support our central hypothesis that post-injury alcohol exposure impairs cognitive and neurobehavioral recovery following TBI. We propose that sustained neuroinflammation is a central underlying mechanism contributing to increased neuronal death and impaired neuroregeneration following TBI. The proposed studies to be performed as part of the training of the applicant will use an integrative approach to test the predictions that 1) post-injury alcohol exposure delays cognitive, behavior, and physical recovery after TBI and that 2) post-injury alcohol exposure prevents resolution of neuroinflammation, accentuates neuronal death, and impairs neurogenesis following TBI. The findings from the proposed study will provide scientific evidence to take necessary interventions during clinical management, which may prevent further alcohol-induced secondary damage and the mechanisms associated with accelerated neurodegenerative changes following TBI.